Phenothiazines as regulators of DNA repair in leukemia

Our aim is to screen a library of phenothiazines and analyze their cytotoxic capacity both as single treatment and in combination with conventional and targeted therapy in acute myeloid leukemia.

Treatment success for patients with acute myeloid leukemia (AML) is very limited. Conventional chemotherapies are limited due to side effects and intrinsic or developed resistance. This resistance is in part a result of increased DNA repair capacity of the leukemic cells and thus sensitizing strategies focusing on DNA repair ablation holds promise. This project is focused on phenothiazines, compounds that are in clinical use for psychiatric disorders already for a long time. We have a library of phenothiazines that are screened in a panel of AML cell lines, both as single treatment and in combination with conventional and targeted therapies. Compounds with cytotoxic capacity are being further analyzed to increase the understanding of DNA damage signaling and apoptosis mechanisms. We will also evaluate our findings in primary AML blast cells.

We have shown that phenothiazines can sensitize solid tumor cells to chemotherapeutics by imparting on the non-homologous end joining DNA repair protein DNA-dependent protein kinase (DNA-PK) and the DNA damage response protein ATM. Phenothiazines have also been linked to resemble histone deacetylase inhibitors. As posttranslational modifications of histones alter chromatin compactness and epigenetic control of chromatin relaxation is altered in hematological malignancies, this offers new therapeutic strategies for AML. Here we aim to further analyze if phenothiazines might cause epigenetic modulation of DNA repair factors and identify novel therapeutic strategies using these compounds.


Chemosensitization by phenothiazines in human lung cancer cells: impaired resolution of γH2AX and increased oxidative stress elicit apoptosis associated with lysosomal expansion and intense vacuolation.
Zong D, Hååg P, Yakymovych I, Lewensohn R, Viktorsson K
Cell Death Dis 2011 Jul;2():e181

Deficient activation of Bak and Bax confers resistance to gemtuzumab ozogamicin-induced apoptotic cell death in AML.
Haag P, Viktorsson K, Lindberg M, Kanter L, Lewensohn R, Stenke L
Exp. Hematol. 2009 Jun;37(6):755-66


Leif Stenke, MD PhD, Department of Oncology-Pathology, Karolinska Institutet.


Stiftelsen för hematologisk forskning